Pharmaceutical composition as solid dosage form and method for manufacturing thereof

ABSTRACT

The present invention relates to a novel pharmaceutical composition as a solid dosage form comprising desmopressin as a therapeutically active ingredient, and to a method for manufacturing thereof. The invention relates to a pharmaceutical composition as a solid dosage form comprising desmopressin, or a pharmaceutically acceptable salt thereof, as a therapeutically active ingredient together with a pharmaceutically acceptable excipient, diluent or carrier, or mixture thereof, wherein at least one of said excipient, diluent and carrier is a substance selected from a monosaccharide, disaccharide, oligosaccharide and a polysaccharide, wherein the said substance has an average particle size in the range of from 60 to 1,000 μm. A method according to the present invention provides an improved production of solid dosage forms of desmopressin.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.10/425,993, filed Apr. 30, 2003, the contents of which are incorporatedherein by reference.

FIELD OF THE INVENTION

The present invention relates to a novel pharmaceutical composition as asolid dosage form comprising desmopressin as a therapeutically activeingredient, and to a method for manufacturing thereof.

TECHNICAL BACKGROUND

Desmopressin, also known as dDAVP, is the therapeutically activeingredient (as its acetate salt) in the pharmaceutical product Minirin®,which is marketed inter alia as a nasal spray and a tablet formulation.Desmopressin is primarily used in the treatment of primary nocturnalenuresis, i.e. bedwetting, in children, but it is approved also for thetreatment of nocturia and diabetes insipidus. The first marketintroduction of the tablet formulation was in Sweden in 1987.

In short, a solid dosage form such as a tablet formulation is typicallymanufactured by compression of a suitable granulate to the desired soliddosage form, where the granulate is composed of the requiredconstituents as a mixture of solid particles. Typical such particles arethe therapeutically active ingredient, various excipients (fillers),disintegrating agents, lubricants and binders, optionally together e.g.with flavoring agent, preservative and/or colorant. The commerciallyavailable Minirin® tablet is prepared according to this generalprotocol, and the tablet was first disclosed as set forth in the patentU.S. Pat. No. 5,047,398, the teachings of which are incorporated hereinby reference. For a comprehensive overview of pharmaceutical tabletmanufacturing, see “Tableting” (by N. A. Armstrong) in“Pharmaceutics—The Science of Dosage Form Design”, pp 647-668; Ed. M. E.Aulton, Churchill Livingstone, Edinburgh, London, Melbourne and NewYork, 1988, the entire teachings of which are incorporated herein byreference.

The Minirin® tablet that is currently marketed, and thus produced inindustrial scale, consists of the therapeutically active ingredientdesmopressin together with potato starch and lactose as excipients, anda suitable amount of binder and lubricant, respectively.

In any tablet compression of a granulate composed of a mixture of solidparticles there is a general need to perform the compressing operationat the highest possible speed while at the same time minimising machinewear and obtaining tablets of a quality that meets the regulatorydemands of all relevant territories.

DISCLOSURE OF THE INVENTION

It has now been discovered that a certain dimension of the excipientparticles unexpectedly provides a substantial improvement on the speedof the manufacturing process, while both machine wear and tablet qualityremain substantially unaltered compared to the industrial manufacturingprocess hitherto used. In essence, the dimension in question seems toaffect the flowability of particles and granulate in such a manner thatit provides an improved overall capacity, and hence speed, in themanufacturing process for the desmopressin tablet formulation.

More specifically, the present invention relates to a pharmaceuticalcomposition as a solid dosage form comprising desmopressin, or apharmaceutically acceptable salt thereof, as a therapeutically activeingredient together with a pharmaceutically acceptable excipient,diluent or carrier, or mixture thereof, wherein at least one of saidexcipient, diluent and carrier is a substance selected from amonosaccharide, disaccharide, oligosaccharide and a polysaccharide,wherein the said substance has an average particle size in the range offrom 60 to 1000 μm.

In those embodiments where there is a mixture of at least two of theaforementioned types of saccharides, at least one of them mustaccordingly be within the specified particle size range of the presentinvention.

In many cases the terms excipient, diluent and carrier can be usedinterchangeably, and they may even refer to one and the same substance,or to a mixture of similar such substances. The proper use andunderstanding of these terms is self-explanatory and lies well withinthe ability of a person skilled in the art of pharmaceuticalformulation.

The pharmaceutical composition according to the present invention mayoptionally comprise at least one additive selected from a disintegratingagent, lubricant, binder, flavoring agent, preservative, colorant and amixture thereof. Where considered suitable also other additives may beincluded. Representative examples of disintegrating agents, lubricants(e.g. magnesium stearate), binders (e.g. Kollidon® 25, BASF), flavoringagents, preservatives and colorants, and suitable mixtures thereof, aswell as any other conventional additive that may be considered by aperson skilled in the art practising the present invention, can be foundin “Handbook of Pharmaceutical Excipients”; Ed. A. H. Kibbe, 3^(rd) Ed.,American Pharmaceutical Association, USA and Pharmaceutical Press UK,2000, the teachings of which are incorporated herein by reference. As anexample, also applicable in the practising of the present invention, itcan be mentioned that typical amounts of lubricants and binders are inthe order of less than 6 percent by weight of the pharmaceuticalcomposition.

As used herein, the expression oligosaccharide relates to a chain, withany degree of branching, of from three to ten monosaccharide unitslinked via glycoside bonds. Accordingly, as used herein, the expressionpolysaccharide relates to a chain, with any degree of branching, of atleast eleven monosaccharide units linked via glycoside bonds.Synthetically modified derivatives and analogues of naturally occurringsaccharides are also possible to use in the practising of the presentinvention.

In the marketed tablet resulting from the hitherto used manufacturingprocess, the lactose particles (Pharmatose 150M provided by DMV, theNetherlands) have an average size of about 50 μm, as determined by anair jet sieve (provided by Alpine GmbH, DE). That particle size does notprovide a granulate that allows a compressing speed exceeding about170,000 tablets per hour (h). In contrast thereto, the process accordingto the present invention allows a compressing speed of up to about250,000 tablets/h with the desired tablet quality and retained low levelof wear on the tabletting machinery.

As further examples of an upper limit for said average particle sizemention can be made of 900, 800, 700 and 600 μm. However, in a preferredembodiment of said pharmaceutical composition, said average particlesize is in the range of from 70 to 500 μm. In another preferredembodiment, said average particle size is in the range of from 75 to 350μm. In yet another preferred embodiment, said average particle size isin the range of from 1100 to 200 μm. In a further preferred embodiment,said average particle size is in the range of from 120 to 180 μm. In themost preferred embodiment of the present invention, said averageparticle size is 140 μm (as measured by an air jet sieve). The lactoseparticles sold as Pharmatose DCL 15, marketed by DMV in the Netherlands,are of this most preferred average particle size. Other particularembodiments may involve use of e.g. Pharmatose DCL 11, Pharmatose DCL 21and Pharmatose DCL 40, all provided by the aforementioned DMV, whichhave an average particle size of 110, 150 and 165 μm, respectively.

According to the commercial provider the particle size distribution ofPharmatose DCL 15 is that essentially all particles have a size below500 μm, whereas approximately 72% of the particles have a size of from75 to 350 μm.

In an air jet sieve measurement of particle size, air is drawn upwards,through a sieve, from a rotating slit so that material on the sieve isfluidised. At the same time a negative pressure is applied to the bottomof the sieve which removes fine particles to a collecting device. Sizeanalyses and determination of average particle size are performed byremoval of particles from the fine end of the size distribution by usingsingle sieves consecutively. See also “Particle Size Measurement”,5^(th) Ed., p 178, vol. 1; T. Allen, Chapman & Hall, London, UK, 1997,for more details on this. For a person skilled in the art, the sizemeasurement as such is thus of conventional character.

Accordingly, it is preferred that said substance is a disaccharide,preferably lactose, and more preferably lactose-.alpha.-monohydrate.

As said polysaccharide, starch is preferred, and of the many availablestarches, potato starch is the most preferred. As examples of potatostarches mention can be made of Pharma M20, Pharma M14 (provided by KMC,DK) and AmylSolVat (provided by Lyckeby Stärkelse AB, SE).

In a preferred embodiment, both said disaccharide and polysaccharide arepresent in the pharmaceutical composition. In that particularembodiment, the weight ratio between said disaccharide andpolysaccharide is typically from 100:1 to 1:100, preferably from 10:1 to1:10, and more preferably from 2:1 to 1:2.

The total combined amount of said excipient, diluent and carrier isusually from 5 to 99, preferably from 50 to 99, percent by weight of thepharmaceutical composition, the balance up to 100% being thetherapeutically active ingredient optionally together with theaforementioned additives, where the latter is preferably lubricant andbinder.

The pharmaceutical composition as a solid dosage form according to thepresent invention is typically a perorally available tablet. As analternative non-limiting embodiment, the said tablet may be adapted fororal, including buccal and/or sublingual, administration.

The composition typically comprises desmopressin acetate in an amount offrom 20 to 600 μg per unit of solid dosage form. As an example, atypical tablet containing 100 μg of desmopressin acetate is white,convex and oval (6.7×9.5 mm) with a thickness of 3-4 mm and a weight of200 mg. As another example, a tablet containing 200 μg of desmopressinacetate is white, round (8 mm diameter) and convex with a thickness of3-4 mm and a weight of 200 mg.

Accordingly, a further aspect of the present invention relates to amethod for the manufacturing of a pharmaceutical composition as a soliddosage form comprising desmopressin, or a pharmaceutically acceptablesalt thereof, as a therapeutically active ingredient, wherein saidmethod comprises the steps of:

-   -   i) mixing desmopressin and an excipient, diluent or carrier, or        mixture thereof, optionally in the presence of a wetting agent,        wherein at least one of said excipient, diluent and carrier is a        substance selected from a monosaccharide, disaccharide,        oligosaccharide and a polysaccharide, wherein said substance has        an average particle size in the range of from 60 to 1000 μm;    -   ii) subjecting the resulting mixture to formation of a        granulate, optionally in the presence of a wetting agent,        suitable for compression into said solid dosage form;    -   iii) optionally performing said mixing and/or formation of a        granulate in the presence of at least one additive selected from        a disintegrating agent, lubricant, binder, flavoring agent,        preservative, colorant and a mixture thereof;    -   iv) optionally drying said granulate;    -   v) compressing said granulate into said solid dosage form.

The method according to the present invention can as such, once thespecific components are identified and included, be practised by usingconventional equipment for the manufacturing of pharmaceuticalformulations. A granulate suitable for compression into tabletstypically has an average granulate size of at least about 100 μm.Discrete granules with a size above 2 mm are usually not transferred tothe subsequent compressing step.

As non-limiting examples mention can be made of the following equipmentfor granulation: directly heated fluidised solid beds e.g. provided byGEA/Collette NV, BE (UltimaPro™ series), Hüttlin GmbH, DE (HDG series),Diosna Dierks & Soehne GmbH, DE (VAC series), Fluid Air Inc., US(Magnaflo® series) and Vector Corp., US (GMX series); indirectconduction moving solids bed, including paddle systems, rotary systemsand agitation systems, which are e.g. provided by Jaygo Inc., US (JRBand Novamix series), Paul O. Abbé Inc., US (Rota-Cone, Rota-U, RotaBlade, Cylindrical Ribbon/Paddle, Plow and Sigma-blade series), ForbergA/S, NO (Forberg II series), Gemco Inc., US (D/3 Double Cone, v-Shapeand Slant-Cone series), LittlefordDay Inc., US (Double Arm, Day Nautaand Daymax series), Patterson-Kelly, Harsco Corp., US (P-K SolidsProcessor® series), Diosna as above (CCS and VAC series), RomacoZanchetta SpA, IT (Rote E, Roto D and Roto P series) and L. B. BohleMaschinen und Verfahren GmbH, DE (Granumator GMA and Vagumator VMAseries); The aforementioned equipment in general also provides drying ofthe prepared granules.

As indicated above, further examples of an upper limit for said averageparticle size are 900, 800, 700 and 600 μm. In a preferred embodiment ofthe method of the present invention, said average particle size is inthe range of from 70 to 500 μm. In another preferred embodiment, saidaverage particle size is in the range of from 75 to 350 μm. In yetanother preferred embodiment, said average particle size is in the rangeof from 100 to 200 μm. In a further preferred embodiment, said averageparticle size is in the range of from 120 to 180 μm. In the mostpreferred embodiment of the present invention, said average particlesize is 140 μm. The lactose particles sold as Pharmatose DCL 15,marketed by DMV in the Netherlands, are of this most preferred averageparticle size. Other possible embodiments of the present method mayinvolve the aforementioned variants of Pharmatose DCL (vide supra).

It is accordingly preferred that said substance is a disaccharide,preferably lactose, and more preferably lactose-a-monohydrate. Saidmonosaccharide may also be D-mannitol, D-sorbitol or xylitol or amixture thereof.

Said polysaccharide is preferably a starch, and more preferably potatostarch. Preferred particular potato starches are the same as thosementioned above.

In the method according to the present invention, the manufactured soliddosage form is typically a perorally available tablet. Where desired, itmay also be in a form and/or composition adapted for oromucosaladministration. Preferred examples of the latter are buccal and/orsublingual administration. Examples of tablet compressing equipmentsuitable for the practising of the present invention are rotary pressesprovided by Elizabeth-Hata International, US (HT series), Courtoy NV, BE(R090F, R100M, RI 90FT, R290FT, R292F and R233 series), Vector Corp., US(2000, 200 and Magna series), Fette GmbH, DE (Hightech, Medium, Specialand WIP series), Manesty, UK (Xpress, Diamond and Value series) andKilian & Co. GmbH, DE (S, T, E, RX and KTS series).

In a preferred embodiment of the present inventive method said steps ofmixing and formation of granulate are performed in a single integratedmachinery that is adapted for such a “one-pot”, i.e. combined, process.An example of such integrated machinery, alternatively denoted one-pot(single pot) equipment, is the FT series, provided by Forberg A/S,Norway.

It is preferred that where used, said wetting agent is selected fromwater and a mixture of water and an alcohol, preferably ethanol. Awater/ethanol 1:3 mixture is typically used, albeit many othercombinations are also possible.

As indicated above, it is preferred that said resulting mixture issubjected to formation of a granulate with an average granulate size ofa least 100 μm, preferably in the range of from 100 μm to 2 mm.

In a preferred embodiment of the method, both said disaccharide andpolysaccharide are present in the mixing step. The weight ratio betweensaid disaccharide and polysaccharide is then typically from 100:1 to1:100, preferably from 10:1 to 1:10, and more preferably from 2:1 to1:2.

The method is preferably performed in such a manner that the totalcombined amount of said excipient, diluent and carrier is from 5 to 99,preferably from 50 to 99, percent by weight of the pharmaceuticalcomposition.

In the most preferred embodiment, desmopressin acetate is used and mixedwith said excipient, diluent and/or carrier in an amount that eventuallyprovides from 20 to 600 μg of desmopressin acetate per unit of soliddosage form (see above and the experimental part for examples of atablet).

In a further aspect, the present invention also relates to apharmaceutical composition as a solid dosage form that is obtainable bythe novel method as defined above, both in general and as outlined inthe specific embodiments.

In order to substantiate and illustrate the present invention in moredetail, the following example is provided. It shall not be construed asa limitation of how the invention may be practised.

EXAMPLE Example 1 Preparation of Solid Dosage Form of dDAVP

Desmopressin acetate (100 or 200 g; provided by PolyPeptide LaboratoriesAB, SE), polyvinyl pyrrolidone (PVP) as binder (1.84 kg; Kollidon® 25provided by BASF GmbH, DE) and granulation liquid (water/ethanol 1:3mixture) are combined in a vessel and mixed at room temperature until aclear solution is achieved. The potato starch (77 kg, average particlesize about 40-50 μm according to laser diffraction measurements;AmylSolVát provided by Lyckeby Stárkelse AB, SE), is weighed and sievedthrough a 2 mm sieve. Lactose (120 kg, DCL 15 provided by DMV NV, NL;see above for the details of this product) is weighed and loadedtogether with the starch into a single pot mixer (FT-350; provided byForberg A/S, NO) and mixed therein. The granulation liquid solution isthen sprayed onto the powder mixture, after which the moist granulate isdried with warm air (150° C.), all with continued mixing. The driedgranulate is then sieved (2 mm) and transferred to a double cone mixer.Magnesium stearate (max 1.0 kg; provided by Peter Greven NV, NL) is thenweighed in, sieved (1 mm) and transferred to the double cone mixer forfinal mixing. Tablets are then compressed from the resulting mixture byusing a conventional rotary tablet compression machine (Kilian S-250),whereby a compressing speed of about 250,000 tablets/h is attainablewith adequate tablet quality and low machine wear. A tablet of adequatequality has a smooth surface without scratches or chipped edges, and itshows no tendencies to lamination (so-called capping).

The process is typically adapted to provide a tablet containing 100 or200 μg of desmopressin acetate with the aforementioned appearance,dimension and weight.

1. A pharmaceutical composition as a solid dosage form comprisingdesmopressin, or a pharmaceutically acceptable salt thereof, as atherapeutically active ingredient together with a pharmaceuticallyacceptable excipient, diluent or carrier, or mixture thereof, wherein atleast one of said excipient, diluent and carrier is a disaccharide,wherein the said disaccharide has an average particle size in the rangeof from 70 to 500 μm, and wherein said solid dosage form is a tablet. 2.The pharmaceutical composition according to claim 1, wherein saidaverage particle size is in the range of from 75 to 350 μm.
 3. Thepharmaceutical composition according to claim 3, wherein said averageparticle size is in the range of from 100 to 200 μm.
 4. Thepharmaceutical composition according to claim 4, wherein said averageparticle size is in the range of from 120 to 180 μm.
 5. Thepharmaceutical composition according to claim 1, wherein saiddisaccharide is lactose.
 6. The pharmaceutical composition according toclaim 1, wherein the total combined amount of said excipient, diluentand carrier is from 5 to 99 percent by weight of the pharmaceuticalcomposition.
 7. The pharmaceutical composition according to claim 1,which comprises desmopressin acetate in an amount of from 20 to 600 μgper unit of solid dosage form.
 8. The pharmaceutical compositionaccording to claim 5, wherein said lactose is lactose-a-monohydrate. 9.The pharmaceutical composition according to claim 6, wherein the totalcombined amount of said excipient, diluent and carrier is from 50 to 99percent by weight of the pharmaceutical composition.
 10. Thepharmaceutical composition according to claim 1, wherein said tablet isadapted for administration by a route selected from the group consistingof oromucosal, buccal and sublingual administration.